Psoriasis and the New Biologic Agents: Interrupting a T-AP Dance

Review Synthèse Psoriasis and the new biologic agents: interrupting a T-AP dance Scott R.A. Walsh, Neil H. Shear Abstract corticosteroids, tar, anthralin, calcipotriol or tazarotene become cumbersome to apply as lesional surface area increases. PSORIASIS IS AN IMMUNE-MEDIATED SKIN DISEASE in which chronic T- Furthermore, potential side effects of these therapies increase cell stimulation by antigen-presenting cells (APC) occurs in the with the level of application. Nevertheless, topical treatment skin. This interplay between the T-cell and APC has been likened remains an adjunct in more severe disease to limit the re- to a “T-AP dance” where specific steps must occur in sequence to quirement for more aggressive therapies. Phototherapy is a result in T-cell activation and the disease phenotype; otherwise T- popular option in the treatment of more widespread disease. cell anergy would occur. Several novel engineered proteins de- However, ultraviolet light is generally only available in larger signed to block specific steps in immune activation (biologic treatment centres, requires a major time commitment (2–3 agents) have demonstrated efficacy in the treatment of psoriasis. times per week for many months) and can be associated with These agents include fusion proteins, monoclonal antibodies and an increased risk of cutaneous neoplasms.6 For moderate to recombinant cytokines. These medications act at specific steps during the T-AP dance either to inhibit T-cell activation, costimu- severe disease, oral systemic immunosuppressives such as lation and subsequent proliferation of T-cells, lead to immune de- methotrexate and cyclosporine or oral retinoids are generally viation or induce specific cytokine blockades. The potential in- the mainstays of therapy. However, because of potentially creased selectivity for specific pathways in immune activation, widespread immunosuppression and possible hepatic or renal clinical efficacy and relative safety of these new agents offers an toxicities, the use of these agents is often limited. alternative for the treatment of moderate to severe psoriasis. Biologic agents are specifically engineered proteins de- signed to block particular immunologic activation steps in- CMAJ 2004;170(13):1933-41 volved in the pathogenesis of psoriasis. They may offer another treatment option for the 10%–35% of people with soriasis is a chronic T-lymphocyte (T-cell) mediated moderate to severe psoriasis. Although the various toxicities inflammatory immune skin disease affecting about of these agents are not yet completely known, it is hoped P 2% of children and adults.1,2 Classified among the that when geared to specific pathways in immune activation, papulosquamous diseases (scaling papules), psoriasis pre- these proteins may result in potentially less widespread im- sents as erythematous, hyperkeratotic, often pruritic, scal- munosuppression. They also may have less hepatic or renal ing papules and plaques (Fig. 1). Among the 4.5 million toxicity than presently available oral agents.7 Although the Americans afflicted with psoriasis, about 65% have mild great expense of these agents (about US$7000 to $20 000 disease (plaques covering less than 2% of the total body surface), 25% have moderate disease (2%–10% of the body area) and 10% have severe disease (> 10% of the body area).3 Although mild to moderate disease may be limited in area, disability can still be severe if the disease is visible on the face or limits mobility of the hands or feet. Psoriasis can dramatically affect psychosocial functioning with increased self-consciousness, frustration, depression, feelings of helplessness and suicidal thought.2 Author John Updike summarized his own battle with psoriasis: “My torture is skin deep … [W]e lepers live a long time … healthy in other respects … we hate to look upon ourselves. [T]he name of the disease … humiliation.”4,5 As psoriasis is a chronic relapsing disease, intermittent treatment may span a lifetime. In order to limit treatment toxicities, the most minimally toxic yet practical approach for the level of body coverage is chosen. An approach to the treatment of psoriasis is shown in Fig. 2. Although highly suc- Fig. 1: Widespread psoriasis. Well-demarcated erythematous DOI:10.1503/cmaj.1031335 cessful in the treatment of mild disease, topical agents such as hyperkeratotic plaque with slight nonconfluent whitish scale. CMAJ • JUNE 22, 2004; 170 (13) 1933 © 2004 Canadian Medical Association or its licensors Walsh and Shear per year) may limit their general accessibility, they currently though initial T-AP interactions occur in lymph nodes (Fig. offer another treatment option for patients for whom sys- 5), ongoing T-AP interactions appear to subsequently occur temic immunosuppressives or phototherapy have failed, or in psoriatic plaques in the skin (Fig. 6).1 The activated T-cells where these treatments are contraindicated because of co- induce secondary hyperproliferation of epidermal, vascular morbid disease. Furthermore, some of these agents appear and occasionally synovial cells through the release of specific to have the potential for sustained clinical remissions, not cytokine mediators such as TNF-α and IFN-γ.1,9 generally seen with our current treatment choices.8 Initiation of the T-AP dance occurs when a specific T- cell receptor on a naïve (CD45 RA+) T-cell (CD4 or CD8) Immunobiology of skin encounters its specific processed antigen presented by the APC in the context of major histocompatibility complex Proinflammatory cytokines such as tumour necrosis fac- proteins (MHC II for exogenous antigens interacting with tor-alpha (TNF-α) or interleukin-1 (IL-1) are not promi- CD4 T-cells or MHC I for endogenous antigens interact- nent in normal skin but can be produced by activated im- ing with CD8 T-cells). Although the nature of the initial mune cells or damaged keratinocytes. They signal the need stimulating antigen in psoriasis is not known, hypotheses for both a reparative and immunologic response (Fig. 3). include a molecular mimicry between streptococcal M pro- Fig. 4 depicts the initial generation of an immune re- teins and human keratins 6 and 17, or the aberrant self- sponse to any foreign antigen in the skin. Antigen-presenting presentation of cutaneous proteins.10,11 Without further cells (APC) mature upon capture of antigen and migrate to APC interaction, this initial interaction would lead to inac- the skin-draining lymph node, where they can activate anti- tivation of the T-cell (i.e., anergy). gen-specific naïve T-cells (see Fig. 5). The mature T-cells In order to prevent T-cell anergy, the APC has costimu- proliferate and express the skin-homing marker, cutaneous latory proteins on its surface that interact with specific T- lymphocyte-associated antigen, which can allow binding to cell proteins that have been up-regulated through T-cell re- the transmembrane endothelial cell adhesion molecules, E- ceptor antigen recognition (Figs. 5 and 7). These molecular and P-selectins. When the activated T-cells release cy- interactions activate the T-cells to become memory CD4 or tokines such as TNF-α and interferon-gamma (IFN-γ), re- CD8 T-cells (CD45 R0+) and induce expression of CD2, generative responses can be initiated and other immune ef- IL-2 and IL-2 receptor (IL-2R or CD25). These latter mol- fector cells recruited, including neutrophils. ecules are necessary for subsequent T-cell proliferation and survival (Fig. 5). T-cells activated in skin-draining lymph The “T-AP” dance of psoriasis nodes also acquire cutaneous lymphocyte-associated antigen, which allows them to interact with E- and P-selectins Psoriasis is an inflammatory disorder where specific T-cell on the endothelial surfaces of the cutaneous vasculature, populations are stimulated by putative antigen presented by thus targeting them to sites of cutaneous inflammation. APC from the skin. Both helper-type T-cells (CD4) and cy- As T-cell activation occurs, 2 distinct lines of differentia- totoxic suppressor-type T-cells (CD8) are involved in psoria- tion are possible. Under the influence of IL-12 or IFN-γ, sis.1 This T-cell/APC (“T-AP”) interaction is much like a tap CD4 T-cells differentiate into a TH1 phenotype and CD8 dance where specific steps must occur in sequence to result in T-cells differentiate into a TC1 phenotype, both with ex- T-cell activation; otherwise T-cell anergy would occur. Al- pression of TNF-α, IL-2 and IFN-γ. This response is asso- Biologic agents Immunosuppressive agents (methotrexate, cyclosporine, etc.) and oral retinoids Phototherapy Topical agents (corticosteroids, tar, anthralin, calcipotriol, tazarotene) Mild Moderate Severe Fig. 2: Approach to the treatment of psoriasis. Topical therapy alone is used to treat mild disease (< 2% of the total body surface area). It becomes adjunctive therapy in moderate (2%–10% of the surface area) and severe (> 10% of the surface area) disease to limit the need for treatments that will be potentially more toxic to the patient. Phototherapy is an option for moderate to severe disease. Immunosuppressive agents and oral retinoids can be considered for widespread moderate and severe disease. The biologic agents represent a newer treatment option for people with this severity of disease. Severe disease also includes body areas that may be limited in extent, but result in functional limitations, such as hand and foot involvement. 1934 JAMC • 22 JUIN 2004; 170 (13) Psoriasis and the new biologics ciated with increased cell-mediated immunity and diseases to present antigen. Instead, the psoriatic plaque begins to such as psoriasis. Alternatively, under the influence of IL-4 act as of a lymph node, with ongoing activation of T-cells or IL-10, CD-4 T-cells differentiate into a TH2 phenotype by APC in the skin itself. Keratinocytes also produce IL-8 and CD8 T-cells differentiate into a TC2 phenotype, both in response to TNF-α, which is chemotactic for neu- with expression of IL-4, IL-6, IL-10 and IL-11.

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